Adipocyte Gata3 Is a Diet-Inducible Driver of Pathological Adipose Remodeling and Systemic Metabolic Disease

Adipose tissue dysfunction drives obesity-associated metabolic disease, yet the transcriptional regulators of pathological adipose remodeling remain undefined. Here, we identify adipocyte Gata3 as a diet-inducible regulator that is dispensable for basal adipogenesis but necessary and sufficient for diet-induced obesity and systemic metabolic dysfunction. Adipocyte-specific Gata3 deletion redirects adipose expansion from hypertrophic to hyperplastic growth and improves glucose tolerance, insulin sensitivity, and adipose inflammation, whereas human GATA3 re-expression in adipocytes restores obesity and metabolic dysfunction, suggesting cross-species conservation and establishing both necessity and sufficiency for a causal driver. Multi-omic profiling, integrating proteomics, metabolomics, and single-cell mass cytometry, reveals that Gata3 loss suppresses a STAT3-anchored inflammatory myeloid program while enhancing mitochondrial oxidative capacity. Through further tracing of this adipocyte-intrinsic program to distal metabolic organs, systemic lipidomic and chemokine profiling identifies a two-pronged mechanism through which adipocyte Gata3 drives hepatic dysfunction: selective remodeling of lipoprotein-surface lipids and a coordinated CXCL5/CXCL2/CXCL9 chemokine axis. Collectively, these findings reposition Gata3 from a putative anti-adipogenic brake to a diet-inducible master regulator of pathological adipose remodeling and nominate adipocyte-targeted Gata3 inhibition as a strategy to uncouple adipose expansion from systemic metabolic disease.